Kinji Hashimoto

Asymmetric synthesis of a xanthine dehydrogenase inhibitor (S)-(−)-BOF-4272: Utility of chiral alkoxysulfonium salts

Abstract A practical synthetic method for a xanthine dehydrogenase inhibitor, ( S )-(−)-BOF-4272, was established utilizing an asymmetric oxidation of diaryl sulfide BOF-4269. The oxidation of the sulfide with 1-chlorobenzotriazole carried out in the presence of 4-cyanopyridine and chiral 2-phenylcyclohexanol gave a high enantiomeric excess (73% ee ). The sulfoxides in each enantiomerically pure form could be obtained by treating with alkaline hydrolysis or thermolysis of one the diastereomeric intermediate sulfonium salts (>99% de ). Thus the transformation into the sulfoxides occur with virtually perfect inversion (alkaline hydrolysis) or retention (thermolysis). It is therefore possible to obtain the target sulfoxide, ( S )-(−)-BOF-4272, from both the two diastereomeric sulfonium intermediates.

Asymmetric Synthesis of a Xanthine Dehydrogenase Inhibitor (S)-(–)-BOF-4272 : Mechanism of Chiral Diaryl Sulfoxide Formation

A pyrazolotriazine derivative (BOF-4272), a potent xanthine dehydrogenase inhibitor, was synthesized in good yield via 9 steps from vanillin. The asymmetric synthesis was achieved effectively by a modified Oaes asymmetric oxidation of diaryl sulfide. A mechanism involving pentacoordinated sulfurane intermediates was supported by the molecular modeling.